WO1998042341A1 - Agent anti-vif - Google Patents

Agent anti-vif Download PDF

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Publication number
WO1998042341A1
WO1998042341A1 PCT/JP1998/001256 JP9801256W WO9842341A1 WO 1998042341 A1 WO1998042341 A1 WO 1998042341A1 JP 9801256 W JP9801256 W JP 9801256W WO 9842341 A1 WO9842341 A1 WO 9842341A1
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Prior art keywords
group
substituted
carbon atoms
methoxy
methyl
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PCT/JP1998/001256
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English (en)
Japanese (ja)
Inventor
Hiroto Kashiwase
Takashi Nishigaki
Tetsushi Katsube
Original Assignee
Sankyo Company, Limited
Ube Industries, Ltd.
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Application filed by Sankyo Company, Limited, Ube Industries, Ltd. filed Critical Sankyo Company, Limited
Priority to AU64218/98A priority Critical patent/AU6421898A/en
Publication of WO1998042341A1 publication Critical patent/WO1998042341A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • feline immunodeficiency virus (Feline immunodeficiency virus (also called Feline T lymphotropic lentivirus)) is hereinafter referred to as FIV.
  • a composition for preventing or treating FIV infection comprising a quinolone carboxylic acid derivative having an activity of inhibiting the growth of FIV infection (cat AIDS); Use of the quinolone carboxylic acid derivative, a salt or ester thereof for the manufacture of a medicament for the prophylaxis or treatment of the above, or the pharmacological activity of the quinolone carboxylic acid derivative, salt or ester thereof
  • the present invention relates to a method for preventing or treating FIV infection (cat age), which comprises administering an effective amount to a warm-blooded animal.
  • Feline immunodeficiency virus is a retrovirus isolated from cats that exhibit symptoms similar to human acquired immunodeficiency syndrome (hereinafter referred to as human aids) [Pedersen, NC et al., Science 235]. , 790-793 (1987)], the human immunodeficiency virus (HIV), the virus that causes human AIDS.
  • FIV causes FIV infection (cat AIDS) by infecting cats.
  • Cat AIDS cat AIDS
  • FIV has been confirmed in cats around the world, and the infection rate varies depending on the survey method.However, 1 to 15% of healthy cats suffer from any disease. It is clear that the percentage of FIV-infected individuals is 3 to 44% in cats that have FIV infection (see Miyazawa, T. and Mikami, TJ Vet. Med. Sci. 55, 519-526 (1993)).
  • EP 584,798 discloses that the following quinolone carboxylate compounds exhibit antiviral activity.
  • the present inventors have intensively studied to find a drug useful as a therapeutic agent or a prophylactic agent for feline AIDS, and as a result, a specific quinolone carboxylic acid derivative has excellent FIV growth inhibitory activity in FIV persistently infected cells, and The present inventors have found that the quinolone carboxylic acid derivative is useful as an active ingredient of a composition for treating or preventing FIV infection (cat AIDS), and have completed the present invention.
  • the present invention relates to a composition for treating or preventing FIV infection (feline AIDS), which comprises a specific quinolone carboxylic acid derivative, a pharmacologically acceptable salt or an ester thereof as an active ingredient, and a FIV infection.
  • Quinolone carboxylic acid derivative for use in the manufacture of a medicament for the prevention or treatment of (cat AIDS) (the use of the present, a pharmaceutically acceptable salt or ester thereof, or the quinolone carboxylic acid derivative,
  • a method for preventing or treating FIV infection (cat AIDS) by administering a pharmacologically effective amount of a salt or an ester thereof to a warm blooded animal.
  • the quinolone carboxylic acid derivative as the active ingredient of the present invention has the following general formula (Ia), (Ib) or (Ic).
  • X represents a hydrogen atom or a halogen atom
  • Y is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an amino group, or 1 to 2 selected from the group consisting of alkyl having 1 to 4 carbons and aralkyl having 7 to 14 carbons Represents a mono- or di-substituted amino group substituted with
  • Z represents an optionally protected carboxy group or 5-tetrazolyl group
  • Q is a nitrogen atom or formula (d) -R2 (d)
  • R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen, or an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen. Which represents an alkoxy group].
  • W represents an oxygen atom or a sulfur atom
  • T represents an alkylene group having 1 to 8 carbon atoms or an alkylene group having 2 to 8 carbon atoms
  • R 1 is a hydrogen atom; an optionally substituted alkyl group having 1 to 4 carbon atoms [substituents of the alkyl group include hydroxy, carboxy, halogen, alkoxy having 1 to 4 carbon atoms, and 3 to 4 carbon atoms. 6 cycloalkyls, 2 to 5 carbon atoms alkanoyloxy, formula (e)
  • R 9 and R 1Q are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R 9 and R 10 are combined to form a bond. Together with a nitrogen atom to form a 3- to 7-membered saturated monocyclic ring containing one or two telo atoms selected from NO and S as the case may be. And a aryl group having 6 to 10 carbon atoms which may be substituted with an R ° group described below.
  • a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, ⁇ and S which may be substituted with a group, or R described below.
  • Cycloalkyl groups an alkoxy group having 1 to 4 carbon atoms; An aryl group having 6 to 10 carbon atoms which may be substituted with a group; 5 to 6 containing 1 or 2 heteroatoms selected from N, ⁇ and S which may be substituted with an R ° group described below.
  • A represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted with halogen, hydroxy or alkoxy having 1 to 4 carbon atoms
  • G represents a nitrogen atom or Equation (g)
  • R is the formula (h) or the formula (i)
  • R 3 and R 6 are R ° (R 0 is halogen, nitro, hydroxy, alkyl having 1 to 4 carbon atoms, carbon atom substituted by fluorine 1 Mono- or dialkyl-substituted amino substituted with 1 to 4 alkyls, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, amino and 1 to 2 alkyls having 1 to 4 carbons R 6 represents an aryl group having 6 to 10 carbon atoms which may be substituted with R. Or a 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S forces which may be substituted with, or R.
  • R 4 , R 5 and R 7 are the same or different and represent a hydrogen atom or a carbon number of 1 to 4
  • R 8 represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms
  • n represents 1 or 2
  • n ′′ represents 1 to 4.
  • Suitable compounds are represented by the general formulas (la-3), (lb-3) and (Ic-3), the general formulas (Ia-4), (Ib-4) and (Ic-4), The following compounds represented by the formulas (Ia-5), (Ib-5) and (Ic-15) and the general formulas (Ia-6) and (Ia-7)
  • R 13 represents an alkoxy group having 1 to 4 carbon atoms (especially a difluoromethyoxy group); and R 13 represents an alkyl group having 1 to 4 carbon atoms which may be substituted by a hydrogen atom, a halogen atom or a halogen (especially fluorine) (especially, A ′ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which may be substituted by a hydrogen atom or halogen (especially fluorine)).
  • the compounds represented by the general formulas (Ia_3), (lb-3), (Ic-3), (la-4) and (Ia-6) are preferable, and more preferably Is a compound represented by general formulas (Ia_3), (la-4) and a general formula (Ia-6) wherein A 'is an alkyl group having 1 to 4 carbon atoms substituted with fluorine, More preferred are the compounds represented by the general formulas (Ia-3) and (Ia-4).
  • the compound in which R 1 is a hydrogen atom has tautomers (IIa) and (IIb) as shown below.
  • the active ingredients of the present invention also include these tautomers.
  • halogen atom of X in the general formulas (Ia), (Ib) and (Ic) a fluorine, chlorine, bromine or iodine atom can be mentioned.
  • fluorine and chlorine atoms more preferably fluorine atoms.
  • X in the general formulas (Ia), (Ib) and (Ic) is preferably hydrogen, fluorine and chlorine atom, more preferably fluorine and chlorine atom, more preferably Is a fluorine atom.
  • Y represents a hydrogen atom; a halogen atom such as fluorine, chlorine, bromine or iodine; a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
  • An alkyl group having 1 to 4 carbon atoms such as; an amino group; methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, benzylamino, phenylamine / amino, Mono- or mono-substituted by one or two substituents selected from the group consisting of alkyl having 1 to 4 carbon atoms and aralkyl having 7 to 14 carbon atoms, such as dibensilamino, di (phenylethyl) amino group; Disubstituted amino groups may be mentioned, preferably hydrogen An atom, fluorine, an amino group, a methyl group and an ethyl group, more preferably a hydrogen atom or an amino group, and most preferably a hydrogen atom.
  • the protecting group for the carboxy group of the “optionally protected carboxy group” of Z in the general formulas (Ia) and (Ic) may be a carboxy protecting group commonly used in organic synthetic chemistry or medicinal chemistry.
  • the ester residue is not particularly limited as long as it is an ester residue usually used as a prodrug, and may be, for example, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl groups; 1 C 7 -C 14 aralkyl groups such as 1-phenylethyl and 1-naphthylmethyl groups; 1- (C 2 -C 8 alkanoyloxy) — C 4 alkyl groups such as acetoxymethyl and bivaloyloxymethyl groups ; 1- (ethoxycarbonyl O carboxymethyl) Echiru, 1-like (isopropoxycarbonyl Cal Boniruokishi) Echiru group 1- (C 1
  • Z in the general formulas (Ia) and (Ic) is preferably a carboxy group which may be protected, and more preferably a carboxy group.
  • the halogen atom of R 2 includes a fluorine, chlorine, bromine or iodine atom; Preferably, they are a fluorine atom and a chlorine atom.
  • the alkyl group having 1 to 4 carbon atoms which may be substituted by halogen of R 2 Alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl groups; fluorine-substituted alkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl and 4-fluorobutyl groups; chloro Methyl, dichloromethyl, trichloromethyl, 2
  • Chloro-substituted alkyl groups such as chloroethyl, 3-chloropropyl and 4-chlorobutyl groups, and are preferably unsubstituted alkyl groups or fluorine-substituted alkyl groups, more preferably methyl, Fluoromethyl, difluoromethyl and trifluoromethyl groups, more preferably a trifluoromethyl group.
  • the alkoxy having 1 to 4 carbon atoms which may be substituted with a halogen of R 2.
  • the group include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups; fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-fluoropropoxy, and 3-fluoropropoxy.
  • Fluorine-substituted alkoxy groups such as xy, 4-fluorobutoxy; 2-chloroethoxy, 2-chloropropoxy, 3-chloropropoxy, 4- Examples include a chlorine-substituted alkoxy group such as a chlorobutoxy group, preferably an unsubstituted alkoxy group and a fluorine-substituted alkoxy group (particularly, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2-fluoroethoxy groups).
  • a chlorine-substituted alkoxy group such as a chlorobutoxy group, preferably an unsubstituted alkoxy group and a fluorine-substituted alkoxy group (particularly, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2-fluoroethoxy groups).
  • R 2 is preferably a hydrogen atom; a halogen atom; An alkyl group having 1 to 4 carbon atoms which may be substituted; an alkoxy group having 1 to 4 carbon atoms which may be substituted by fluorine, more preferably, fluoromethyl, difluoromethyl, trifluoromethyl, Methoxy, difluoromethoxy and trifluoromethyl groups, more preferably methoxy, difluoromethoxy and trifluoromethyl groups, and most preferably difluoromethoxy and trifluoromethyl groups.
  • Q in the general formulas (Ia), (Ib) and (Ic) is preferably a formula (d) in which R 2 in the formula (d) is a difluoromethoxy or trifluoromethyl group.
  • W in the general formula (Ib) is preferably a sulfur atom.
  • T is, for example, 1 carbon atoms such as methylene, ethylidene [1-CH (CH 3 ) 1], ethylene, trimethylene, propylene, tetramethylene, butylene, pentylene, hexylene, and octylene.
  • alkenylene group having 2 to 8 carbon atoms preferably an ethylidene group, —CH ⁇ ⁇ CH— and —C (CH 3 ) CH— groups, and more preferably an ethylidene group.
  • examples of the “C1 to C4 alkyl group” of the optionally substituted C1 to C4 alkyl group for R 1 include, for example, methyl, And alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups, preferably methyl, ethyl, propyl and isopropyl groups. Methyl, ethyl and isopropyl groups, most preferably a methyl group.
  • Examples of the halogen atom as a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 in the general formulas (Ia) and (Ib) include a fluorine, chlorine, bromine or iodine atom; Preferred are fluorine and chlorine atoms, and more preferred are fluorine atoms.
  • Examples Ebame butoxy examples include ethoxy, propoxy, isopropoxy and butoxy groups, preferably methoxy and ethoxy groups, more preferably methoxy groups.
  • examples of the cycloalkyl group having 3 to 6 carbon atoms which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 include cyclopropyl, Examples include a cyclobutyl, cyclopentyl or cyclohexyl group, and a cyclopropyl group is preferred.
  • R 1 is a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms.
  • a propionyloxy or brityloxy group preferably an acetoxy group.
  • R 1 has 1 to 4 carbon atoms.
  • the alkyl group having 1 to 4 carbon atoms of R 9 and R 1 Q in the formula (e), which is a substituent of the alkyl group, is described as the alkyl group having 1 to 4 carbon atoms of R 1. And the like, and preferably, methyl and ethyl groups.
  • R 9 and R 1 Q in the above formula (e), which are substituents of R 1 substituted alkyl groups having 1 to 4 carbon atoms, are taken together.
  • R 1 is a substituent of a substituted alkyl group having 1 to 4 carbon atoms
  • the formula (e) is preferably amino, methylamino, Dimethylamino, piperidino and morpholino groups, more preferably dimethylamino groups.
  • R 1 is a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and “R 6 may be substituted with 6 to 10 carbon atoms.
  • R 6 may be substituted with 6 to 10 carbon atoms.
  • Examples of the "aryl group having 6 to 10 carbon atoms" portion of the "aryl group” include phenyl, 1-naphthyl, and 2-naphthyl groups, and a phenyl group is preferable.
  • R 1 is a substituent of a substituted alkyl group having 1 to 4 carbon atoms, and is selected from N, O and S which may be substituted with R.
  • Group '' and ⁇ heteroaromatic condensed ring group '' part examples include, for example, 2-thienyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazyl, 2-benzoxazolyl, 2-benzothiazolyl, 2- Benzoimidazolyl, 3-benzoisoxazolyl, 3-benzoisothiazolinole group and the like are preferred, preferably 2-phenyl, 2-furyl, 2-pyridyl and 2-pyrimidinyl groups.
  • R which is a substituent of the substituted alkyl group having 1 to 4 carbon atoms of R 1 in the general formulas (Ia) and (Ib).
  • R Q of an aryl group having 6 to 10 carbon atoms and a heteroaromatic group which may be substituted with, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; a nitro group; Droxy group; alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isoptinole, t-butyl group; fluoromethyl, difluoromethylinole, trifluoromethyl, 2-fluoroethyl , 2-fluoropropyl, 3-fluoropropyl, 2-fluorobutynole, 3-fluorolenobutyl and 4-fluoro
  • a dialkyl-substituted amino group substituted by an alkyl group having 1 to 4 carbon atoms such as dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, and ethyl (methyl) amino;
  • R 1 as the whole optionally substituted alkyl group having 1 to 4 carbon atoms is preferably methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl; 2-hydroxyl, 2-hydroxypropyl, 3-hydroxypropyl; carboxymethinole,-1-canoleboxixyl, 2-canoleboxille; funo Leolomethinole, Chloromethinole, 2-Funoleronitinole, 2-Chloroechinole, 2-Bromoethinole, 2-Yo-doethynole, 3 —Pronoole with phenolic mouth, 3-propinole with chlorophyll, 3-Bromopropinole, 4-Funolenobutyl, Diphnoleolomethinole, tribunoolelomethinole, 2,2,2-triflu
  • alkenyl group having 2 to 5 carbon atoms which may be substituted with a halogen for R 1 in the general formulas (la) and (lb) include, for example, bier, 2_propenyl, 1-butenyl, 2-butenyl , 3-butel, 3,3-dimethyl-2-propionyl, 2-fluorovinyl, 2- (2-funoleo port) propinole, 3,3-difluoro-2-propionyl, 3,3-dicrochloride-2 —Vinyl, 2-propenyl, 3,3-dimethyl-2-propyl and 3,3-dichloro-12-propyl, more preferably Include a bullet and a 2-propenyl group.
  • Examples of the alkynyl group having 2 to 4 carbon atoms for R 1 in the above general formulas (Ia) and (Ib) include a carbon number such as ethur, 1-propynyl, 2-propenyl, and 2-butynyl group. Examples thereof include 2 to 4 alkynyl groups, preferably ethynyl and 2-propenyl, and more preferably 2-propynyl.
  • examples of the mono- or dialkyl-substituted amino group substituted with 1 to 2 alkyl groups having 1 to 2 carbon atoms for R 1 include methylamino, ethylamino, propylamino, Monoalkyl-substituted amino groups such as isopropylamino and butylamino groups; dialkyl-substituted amino groups such as dimethylamino, methylamino, dipropylamino, diisopropylamino and dibutylamino groups, and preferably, methylamino, ethylamino and dimethylamino groups. And more preferably a methylamino group.
  • Examples of the cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a halogen of R 1 in the general formulas (Ia) and (Ib) include, for example, cyclopropyl, cycloptinole, cyclopentinole, cyclohexinole , 2-Funoleolocyclopropinole, 2-Chlorocyclopropinole, 2-Bromocyclopropione, 2,2-Diphneolocyclopropinole, 2-Clot mouth_2-Funoleolocyclopropinole, 2 —Funoleolocyclobutynole, 2-Funoleolocyclopentinole, 2-Fusleolocyclohexynole group, and the like.
  • cyclopropyl Preferred are cyclopropyl, cyclobutyl, and cyclopentyl. And 2-fluorocyclopropyl group, more preferably a cyclopropyl group.
  • alkoxy group having 1 to 4 carbon atoms of R 1 in the general formulas (Ia) and (Ib) include alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • methoxy, ethoxy and propoxy groups more preferred are methoxy and ethoxy groups.
  • Formula (I a) and (I b) in the "but it may also be substituted by R.
  • R 1 may be an “aryl group having 6 to 10 carbon atoms, which may be substituted with R.” or “N, which may be substituted with R.
  • a halogen atom an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms. It is preferably at least 4 alkoxy groups, particularly preferably a fluorine atom, a chlorine atom, a methyl group or a methoxy group.
  • R 1 in the above general formulas (Ia) and (Ib) is preferably a hydrogen atom; an optionally substituted alkyl group having 1 to 4 carbon atoms (the substituents are hydroxy, carboxy) , Fluorine, chlorine, methoxy, ethoxy, cyclopropyl, acetoxy, amino, methylamino, dimethylamino, piperidino, morpholino, or phenyl, phenyl, phenyl, frill optionally substituted by fluorine, chlorine, methyl or methoxy , Pyridyl or pyrimidinyl); vinyl, 2-propenyl, 3,3-dimethyl-12-propyl, 3,3-dichloro-12-propenyl, ethl, 2-propenyl; amino group A mono- or di- (methyl or ethyl) -substituted amino group; a cycloalkyl group having 3 to 6 carbon atoms which may be substituted by fluor
  • a hydrogen atom methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butynole 2-hydroxyhexinole, 2-hydroxypropinole, 3-hydroxypropyl canolepoxymethinole, 1-canole Reboxetinole, 2-force Noreboxetinole; Funorelomethinole, 2-Fuzoleolochinole, 2-Chlorochinole, 3-Fluoropropyl, 3-Chloropropyl, Difluoromethyl, Trinolemethylo, 2 Cyclopropylmethyl; 2-acetoxityl, 2-acetoxypropyl, 3-acetoxypropyl; 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2,2-trifluoroethyl; 2-Monole holinoethyl, 2-piperidinoethyl, 2-pipe
  • the “halogen” of A in the formula (f) examples include methyl, ethyl, propyl, isopropyl, and butyl groups.
  • Alkyl group Fluoromethyl, methyl methyl, diphnoleolomethinole, trifnoleolomethinole, 2-phnoleoletinole, 2-chloroethyl, 2-bromoethyl, 2-propeneole, 3-propeneole, propylenopropyl, Halogeno-substituted alkyl groups such as 2-funoleolobutinole, 3-funoleolobutinole, 4-fluorobutynole; hydroxymethyl, 2-hydroxylshethyl, 3-hydroxyl Hydroxy-substituted alkyl groups such as oxypropyl and 4-hydroxybutyl groups; and alkoxy-substituted alkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyshetyl, methoxypropyl, and methoxybutyl groups.
  • alkyl group having 1 to 4 carbon atoms of R 11 of one N (R 11 ) — of G 1 in the formula (f) methyl, Ethyl, propyl, isopropyl, butyl, etc., preferably methyl and ethyl, and G 1 in the formula (f) is preferably an oxygen atom and a sulfur atom, more preferably Is an oxygen atom.
  • R 1 and R 2 together form the formula (Ia).
  • p in the formula (f) is preferably 1.
  • R is a substituent of a substituted alkyl group having 1 to 4 carbon atoms of R 1 in the aforementioned general formulas (Ia) and (Ib). May be substituted with R in the heteroaromatic ring group.
  • a fluorine or chlorine atom nitro; hydroxy; methyl, ethyl; trifluoromethyl; methoxy, ethoxy; methylthio, ethylthio; amino, methylamino, dimethylamino; More preferably, they are a fluorine atom, a chlorine atom, a methyl, a trifluoromethyl, a methoxy or a methylthio group.
  • the aryl groups having 6 to 10 carbon atoms of R 3 and R s in the formulas (h) and (i) of R in the general formulas (Ia), (Ib) and (Ic) include phenyl, Examples thereof include 1-naphthyl and 2-naphthyl groups, and a phenyl group is preferable.
  • heteroaromatic group of R 3 and R 6 in the formulas (h) and (i) of R in the general formulas (Ia), (Ib) and (Ic) include, for example, 2-Chenyl, 2- Furyl, 2-oxazolyl, 2-thiazolyl, 2-midazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-benzoxazolinole , 2-benzothiazolyl, 2-benzoimidazolyl, 3-benzoisoxazolyl, and 3-benzoisothiazolyl groups.
  • 2-thiazolyl 4-pyrimidinyl, 2-pyrazinyl, and 3-benzoisothiyl.
  • Azolyl, 2-pyridinole, 2-pyrimidinyl, 2-benzothiazolyl and 2-benzoxazolyl groups more preferably 2-thiazolyl, 2-pyrimidinyl 2-pyridyl, 2-base Nzochiazoriru and 2-benzo O hexa benzotriazolyl group.
  • R 3 and R 6 in the above preferably an optionally substituted phenyl, pyridyl, pyrazinyl, pyrimigel, thiazolyl, benzothiazolyl, benzoisothiazolyl and benzoxazolyl group (the substituent is fluorine, chlorine, nitro , Hydroxy, methinole, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino or dimethylamino).
  • alkyl group having 1 to 4 carbon atoms of R 4 , R 5 and R 7 in the formulas (h) and (i) of R in the general formulas (Ia), (Ib) and (Ic) examples include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropynole, butynole, isoptinole, s-butyl and t-butyl, and preferably methyl, ethyl, propyl And isopropyl groups, particularly preferably methyl and ethyl groups.
  • alkyl group having 1 to 4 carbon atoms of R 8 in the formula (i) of R in the general formulas (Ia), (Ib) and (Ic) include, for example, methyl, ethyl, propyl, isopropyl, Alkyl groups such as butyl, isobutyl and t-butyl groups are mentioned, preferably methyl, ethyl, propyl and isopropyl groups, and more preferably methyl and ethyl groups.
  • alkoxy group having 1 to 4 carbon atoms of R 8 in the formula (i) of R in the general formulas (Ia), (Ib) and (Ic) include, for example, methoxy, ethoxy, propoxy, isopropoxy, Alkoxy groups such as butoxy groups are mentioned, and methoxy, ethoxy and propoxy groups are preferred.
  • R 8 in the formula (i) of R in the general formulas (Ia), (lb) and (Ic) is preferably a hydrogen atom, a hydroxyl group, methyl, ethyl, propyl, iso A propyl, methoxy, ethoxy and propoxy group, more preferably a hydrogen atom, a hydroxyl group, methyl, ethyl, methoxy and ethoxy group (particularly a hydrogen atom).
  • n is preferably 1, and in the formula, the sum of n ′ and n ′′ is 3 , 4 or 5 is preferable, and particularly preferably 3 or 4.
  • m is preferably 0.
  • R in I c) is preferably a group represented by the formula (h) (wherein R 3 , R 4 and R 5 are as defined above), and more preferably a group represented by the formula (h) A group represented by the formula [wherein, R 3 is an aryl group having 6 to 10 carbon atoms which may be substituted with R., a heteroatom selected from N, ⁇ and S which may be substituted with R. A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 or a heteroaromatic condensed ring group obtained by condensing a benzene ring with these heteroaromatic monocycles optionally substituted with R.
  • R 4 and R 5 is the same or different and represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n represents 1.
  • R 3 is an optionally substituted phenyl, pyridyl, virazyl, pyrimigel, thiazolyl, benzothiazolyl, benzoisothiazolyl or benzoxazolyl group
  • the substituted group is fluorine, chlorine, nitro, human Dorokishi, methyl, Echiru, triflumizole Ruo Russia methyl, main butoxy represents ethoxy, methylthio, Echiruchio, Amino, the a is) Mechiruamino or dimethylaminopyridine amino group
  • R 4 and R 5 are the same Or differently represents a hydrogen atom or a methyl group, and n represents 1.
  • 4- (phenyl) pirazin-1-yl, 4- (4-fluorophenyl) pirazin-1-yl, 4- (2-thiazolyl) piperazine-1-yl , 4- (2-pyrimidel) piperazine-1 -yl, 4- (2-benzothiazolyl) piperazine-1 -yl, 4- (2-benzoxazolyl) piperazine-1 —Yl and 4- (2-pyridyl) pirazazine are 1-yl groups.
  • the carbonyl group may be protected by a protecting group to form an ester, Examples of such a protecting group include the same as those described above for the “optionally protected carboxylic group” of Z.
  • the compounds represented by the above general formulas (Ia), (Ib) and (Ic) can be pharmacologically acceptable salts, if necessary.
  • Such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; methanesulfonate, ethanesulfonate, benzene Acid addition salts of organic acids such as sulphonates, p-toluenesulphonates, oxalates, maleates, fumarates, tartrates, citrates; or sodium, potassium, calcium salts, Metal salts of carboxylic acids such as magnesium salts, manganese salts, iron salts and aluminum salts.
  • the compounds (Ia), (Ib) and (Ic) of the present invention can also exist as hydrates.
  • Preferred compounds among the compounds of formulas (Ia), (Ib) and (Ic) which are the active ingredients of the present invention include, for example, the following compounds.
  • Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group
  • Q is the formula (d), and R 2 in the formula (d) is an alkyl group having 1 to 4 carbon atoms or fluorine which may be substituted by a hydrogen atom, a halogen atom or a fluorine atom.
  • R 2 in the formula (d) is an alkyl group having 1 to 4 carbon atoms or fluorine which may be substituted by a hydrogen atom, a halogen atom or a fluorine atom.
  • R 1 is a hydrogen atom; an optionally substituted alkyl group having 1 to 4 carbon atoms (the substituent is hydroxy, carboxy, fluorine, Chlorine, methoxy, ethoxy, cyclopropyl, acetoxy, amino, methylamino, dimethylamino, piperidino, morpholino, or phenyl, phenyl, phenyl, phenyl, pyridyl or phenyl optionally substituted by fluorine, chlorine, methyl or methoxy Pirimigel); bur, 2-propenyl, 3, 3 1-dimethynole-1-propininole, 3,3-dichloro-1--2-propeninole; ethininole, 2-propynyl; amino group; mono- or di- (methyl or ethyl) -substituted amino group; substituted by fluorine A cycloalkyl
  • R 1 is a hydrogen atom, methyl, ethyl, propinole, isopropinole, butynole, s-butynole, t-butynole, 2-hydroxyethylezole, 2-hydroxypropine Nore, 3-hydroxypropinole, canoleboximetinole, 1-carboxyethyl, 2-carboxyethyl, fluoromethyl, 2-funoroletyl, 2-chloroethyl, 3-fluoropropynole, 3-propanolinole , Difluoromethyl, trifnoroleolomethyl, 2,2,2-trifnoreloethyl, cyclopropylmethyl, 2-acetoxityl, 2-acetoxoxypropyl, 3-acetoxoxypropyl, 2-aminoethyl, 2- Methylaminoethyl, 2-dimethylaminoethyl
  • R 1 represents a hydrogen atom, methyl, ethyl, propyl, isopropyl, 2-hydroxyxethyl, canolepoxymethyl, 2-fluoroethyl, 2-chloroethynole , 2,2,2-tri-Fenoleolochinole, 2-acetoxicetyl, phenylmethyl, 2-phenylethyl, 2-pyridylmethyl, 2-dimethinoleaminoethyl, 2-monoreholenotine, vinylinole, 2 —Propaninole, 2-propynyl, amino, methylamino, methoxy, cyclopropyl, cyclobutynole, cyclopentinole, 2-funoleolocyclopropinole, feninole, 2-funole oropheninole, 3 —funoleolofeni
  • R 22 is a group represented by the formula (h) wherein R 3 is R.
  • R 3 is R.
  • R 4 and R 5 are the same or different and are a hydrogen atom or an alkyl having 1 to 4 carbon atoms.
  • R is a group represented by the formula (h): wherein R 3 is a phenyl, pyridyl, pyrazyl, pyrimidinyl, thiazolyl, benzothiazolyl, benzoisothiazolyl or benzoxazolyl group which may be substituted; substituent denotes fluorine, chlorine, nitro, human Dorokishi, Mechinore, Echinore, triflumizole Honoré Oro methylate Honoré, main butoxy, ethoxy carboxymethyl, methylthio, Echiruchio, Amino, the a is) Mechiruamino or Jimechiruamino group, R 4 and R 5 Are the same or different and represent a hydrogen atom or a methyl group, and n represents 1.]
  • R is 4_ (ferru) piperazine-1 -yl, 4- (4-fluorophenyl) piperazine-1 -yl, 4- (2-methoxyphenyl) piperazine-1 —Yl, 4— (2-thiazolyl) piperazine 1 1-yl, 4— (2-pyrimidinyl) piperazine 1 1-yl, 4_ (2—benzothiazolyl) piperazine 1 1 1-yl, 4- (2-benzoxazolyl) piperazine-1 1-yl, 4- (6—methoxy-1-2-benzoxazolyl) piperazine-1 1-yl, 4 — (6-Methoxy-2-benzothiazolyl) pirazin-1-yl or 4- (2-pyridyl) pirazin-1-yl compound,
  • a compound represented by the formula (Ia) (where X is a fluorine or chlorine atom, Y is a hydrogen atom, a fluorine atom, an amino group, a methyl group or an ethyl group, and Z is protected Is a good carboxy group, Q is the formula (d), and R 2 in the formula (d) is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom or fluorine.
  • R 1 is a hydrogen atom; an alkyl group having 1 to 4 carbon atoms which may be substituted; A kill group (the substituent is substituted with hydroxy, carboxy, fluorine, chlorine, methoxy, ethoxy, cyclopropyl, acetoxy, amino, methylamino, dimethylamino, piperidino, morpholino, or fluorine, chlorine, methyl or methoxy) Phenyl, phenyl, thienyl, furyl, pyridyl or pyrimidinyl); vinyl, 2-propenyl, 3,3-dimethyl-2-propenyl, 3,3-dichloro-1-propenyl; Ethyl, 2-propyninole; amino group; ⁇ mono- or di- (methyl or ethyl) -substituted amino group; cycloalkyl group having 3 to 6 carbon atom
  • R An aryl group having 6 to 10 carbon atoms, which may be substituted by R; A 5- or 6-membered heteroaromatic monocyclic group containing 1 or 2 heteroatoms selected from N, O and S, which may be substituted with, or R.
  • R 4 and R 5 are the same or different and are a hydrogen atom or an alkyl having 1 to 4 carbon atoms.
  • R 1 is a hydrogen atom, methynole, ethyl, 2-hydroxyethyl, 2-fluoroethyl, cyclopropyl or isopropyl group
  • R is a group represented by the formula (h), wherein R 3 is Phenyl, pyridyl, bi Jil, pyrimigel, thiazolyl, benzothiazolyl, benzisothiazolyl or benzoxazolyl group (the substituents are fluorine, chlorine, nitro, hydroxy, methyl, ethyl, trifluoromethylinole, methoxy, ethoxy, methinorethio, ethinolethione) , Mechinorea R 4 and R 5 are the same or different and each represents a hydrogen atom or a methyl group, and n represents 1.]
  • R 2 is a difluoromethoxy or trifluoromethyl group;
  • R 1 is a methyl group;
  • R is 4- (phenyl) piperazine-11-yl; 4- (4-fluorophenylene) 1-yl, 4_ (2-methoxyphenyl) piperazine 1-yl, 4- (2-thiazolyl) 1-yl piperazine, 4- (2-pyrimidinole) Piperazine 1-inole, 4- (2-Benzothiazolinole) Piperazine 1-11, 4- (2-benzoxazolyl) Piperazine 1-inole, 4- (6-me Toxic-2-benzobenzozolinol) piperazine 1-inole, 4- (6-methoxy-2-benzothiazolyl) piperazine 1-yl or 4- (2-pyridyl) pidazin
  • Nono 2 Chlorophenyl Nono 2-1-Chlorophenyl Nono 3 'Sono' Nono 3-1-Nono
  • Nono 2 1 Birimidinyl ⁇ 2 Pyrimidinyl Nono 4! 1 Nono 4
  • Nono 2-methylthiophenyl Nono 2 Metal Organic Chemical Vaporous styrene
  • Method for styrene Nono 2-methylthiophenyl Nono 2 —Methylthiophenyl Nono 3 11 Nono 3 ⁇ Nono Nono 4 11 Nono 4 ⁇ 1) Nono 2-ethylthiophenidyl Nono-2-ethylthiophenidyl Nono 3 II No / 3-! )
  • Suitable compounds represented by the general formula (Ia), (Ib) or (Ic), which are the active ingredients of the present invention, include:
  • 6-Fluoro-7 [4- (4-Fluorophenyl) piperazine-1-inole]-1,4-Dihydro_1-methinole-8-Trifrenoleolomethinole-1 4-oxoquinoline-3 Acid,
  • 6-Funoleo mouth _ 7 [4- (4-Funoleo mouth phenyl) piperazine-11-yl] 1,1,4-dihydro-1-1-Methyl-1-oxoquinoline-3-Carbon Acids, and
  • 6-Fluoro-7 [4- (4-Fluorophenyl) piperazine-1-inole] _ 1,4-Dihydro-1- 1-Methyl-1 8-Triphnorelolomethyl-1 4-Oxoquinoline-1 3-Capitol Acid,
  • the quinolone carboxylic acid derivative which is an active ingredient of the present invention, significantly suppresses feline immunodeficiency virus (FIV) proliferation at a low concentration, shows low cytotoxicity, and shows good oral absorption. Therefore, a composition containing the quinolone carboxylic acid derivative as an active ingredient is useful as an agent for treating or preventing FIV infection (cat AIDS).
  • the dosage form of the feline AIDS therapeutic or prophylactic agent of the present invention include oral administration by tablets, capsules, granules, powders, syrups and the like, and parenteral administration by injections or suppositories.
  • excipients eg, lactose, sucrose, glucose, saccharide derivatives such as mannitol, sorbitol; corn starch, potato starch, starch derivatives such as ⁇ -starch, dextrin; Organic excipients such as arabia gum; dextran; pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; phosphoric acid Phosphates such as calcium hydrogen; carbonates such as calcium carbonate; calcium sulfate And inorganic excipients such as sulfates, etc.), lubricants (eg, metal stearate such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; Boxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid
  • binders for example, hydroxypropyl senorelose, hydroxypropinolemethinoresenololose, polyvinylinolepyrrolidone, macrocrogol, and compounds similar to the above-mentioned excipients).
  • Disintegrants for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethyl cellulose, canoleboxime methisolesenolate, scanolesome, and internally crosslinked canoleboxime methylose cellulose; sunatumium; carboxymethyl Starch, cellulose and cellulose modified chemically such as sodium starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben); chlorobutanoic acid No Alcohols such as benzinoleanolone and feninoleethenoleanolecone; benzalcoum chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.) and diluents can be produced by
  • the dose of the therapeutic or prophylactic agent for feline AIDS of the present invention can vary greatly depending on various conditions such as the activity of each drug, the symptoms, age, and weight of the affected animal. It can be lmg (preferably 5 mg), up to 100 mg (preferably 50 mg).
  • N 10% of the FIV persistently infected cell line P-CRFK, which was prepared by infecting the ⁇ ⁇ Itodatsuki wrapping strain CRFK (American Type Culture Collection No. CCL 94) with the FIV Petaluma strain, was added to DMEM (manufactured by Gibco BRL). The cells were cultured in a medium supplemented with fetal calf serum (hereinafter referred to as serum medium) in the presence of 10% carbon dioxide at 37 ° C.
  • serum medium fetal calf serum
  • the cells attached to the flask used for the culture were washed with phosphate-buffered saline— (2.9 g Z liter containing disodium hydrogen phosphate decahydrate, containing 8 g / l sodium chloride, 0.2 g After washing 3 to 4 times with gram / liter of potassium dihydrogen phosphate and 0.2 gram of potassium phosphate (hereinafter referred to as PBS), trypsin EDTA solution (manufactured by Gibco BRL) The cells were detached by, a small amount of serum medium was added, and the cells were collected by centrifugation. The recovered cells were suspended in 1 X 1 0 5 cells / Miriritsu made to take as serum culture areas.
  • phosphate-buffered saline— 2.9 g Z liter containing disodium hydrogen phosphate decahydrate, containing 8 g / l sodium chloride, 0.2 g
  • trypsin EDTA solution manufactured by Gibco BRL
  • the anti-FIV p24 mouse monoclonal antibody F2710 was diluted to 2 micrograms / milliliter with 0.1 M carbonate buffer (pH 9.6), and 100 microliters of each solution were added to a 96-well ELISA plate (Maxisorp, Nunc). The mixture was dispensed into the wells, and left at 4 ° C. overnight to allow the antigen to be adsorbed to the bottom of the plate wells. play After washing the plate three times with PBS, 200 ⁇ l of 0.1 M carbonate buffer (pH 9.6) containing 1 (w / v) bovine serum albumin was added to each well and incubated at 37 ° C for 1 hour. .
  • the substrate solution [1 mg / milliliter of 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid diammonium salt), 1 microliter Tol / milliliter of McIlvaine buffer containing 30% aqueous hydrogen peroxide (pH 4.0, adjusted to pH 4.0 by mixing 0.1 M citrate solution and 0.2 M sodium hydrogen phosphate 2 sodium solution) was added at 100 microliters / well, and incubated at 25 ° C for 20 minutes, 1N sulfuric acid was dispensed at 50 microliters / well, and the reaction was stopped. (Manufactured by Bio-Rad) to measure the absorbance at 405 nm. A reference wavelength of 492 nanometers was used.
  • the purified recombinant FIVp24 standard sample diluted to 0, 200, 400, 600, 800, and 1000 picograms / milliliter was measured.
  • the concentration of the standard sample was plotted on the vertical axis, and the absorbance was plotted on the horizontal axis.
  • the results obtained with the standard sample were plotted on a graph, and then a regression line was created. From the obtained regression line, the value in each sample was calculated. 24 The amount of antigen was calculated. That is, the regression line is
  • the amount of p24 antigen in the sample is
  • the virus production rate in the presence of the test compound was calculated by the following equation.
  • a compound having a virus production rate of about 20% or less at a compound concentration of 1 microgram Z milliliter was defined as a positive compound.
  • the virus production rate at each compound concentration was examined in accordance with the above-mentioned methods (1) to (3).

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Abstract

La présente invention concerne une composition destinée à guérir ou à prévenir les maladies infectieuses à virus de l'immunodéficience féline (VIF) (SIDA félin) et contenant, comme principe actif, un dérivé d'acide quinolonecarboxylique ou un sel ou un ester de ce dernier, chacune de ces substances déployant une excellente activité anti-VIF. Ce dérivé est représenté, par exemple, par la formule générale dans laquelle X est un hydrogène ou un halogéno; Y est un hydrogène, un halogéno, alkyle, etc.; Z est un carboxy facultativement protégé, etc.; Q est un azote, un C-H, C-CF3, C-OCF2H, etc.; R1 est un hydrogène, un alkyle, etc.; et R est un groupe pipérazine substitué par un groupe aromatique facultativement substitué, etc.
PCT/JP1998/001256 1997-03-25 1998-03-24 Agent anti-vif WO1998042341A1 (fr)

Priority Applications (1)

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JP7166997 1997-03-25
JP9/71669 1997-03-25

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60202822A (ja) * 1984-03-28 1985-10-14 Dai Ichi Seiyaku Co Ltd 抗ウイルス薬
JPS63145268A (ja) * 1986-12-03 1988-06-17 バイエル・アクチエンゲゼルシヤフト キノリンカルボン酸類の製造方法
WO1990013542A1 (fr) * 1989-04-28 1990-11-15 Daiichi Pharmaceutical Co., Ltd. Medicament anti-hiv
JPH06116241A (ja) * 1992-05-27 1994-04-26 Ube Ind Ltd アリール基又は複素芳香環基置換アミノキノロン誘導体及びエイズ治療剤
JPH08183775A (ja) * 1994-07-18 1996-07-16 Sankyo Co Ltd トリフルオロメチルキノリンカルボン酸誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60202822A (ja) * 1984-03-28 1985-10-14 Dai Ichi Seiyaku Co Ltd 抗ウイルス薬
JPS63145268A (ja) * 1986-12-03 1988-06-17 バイエル・アクチエンゲゼルシヤフト キノリンカルボン酸類の製造方法
WO1990013542A1 (fr) * 1989-04-28 1990-11-15 Daiichi Pharmaceutical Co., Ltd. Medicament anti-hiv
JPH06116241A (ja) * 1992-05-27 1994-04-26 Ube Ind Ltd アリール基又は複素芳香環基置換アミノキノロン誘導体及びエイズ治療剤
JPH08183775A (ja) * 1994-07-18 1996-07-16 Sankyo Co Ltd トリフルオロメチルキノリンカルボン酸誘導体

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